US5064849A - Heterocyclic derivatives useful as radiosensitizing agents and antiviral agents - Google Patents

Heterocyclic derivatives useful as radiosensitizing agents and antiviral agents Download PDF

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US5064849A
US5064849A US07/510,869 US51086990A US5064849A US 5064849 A US5064849 A US 5064849A US 51086990 A US51086990 A US 51086990A US 5064849 A US5064849 A US 5064849A
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compound
agents
radiosensitizing
antiviral
derivative
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Toshimitsu Suzuki
Masakazu Sakaguchi
Yoshiyuki Miyata
Tomoyuki Mori
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Pola Chemical Industries Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to a novel heterocyclic derivative of formula (I): ##STR5## wherein R 1 represents ##STR6## and R 2 represents a hydrogen atom or an acyl group; its preparation; and radiosensitizing agents and antiviral agents comprising the derivative as their active component.
  • hypoxic cells in tumor tissues are strongly resistant to radiation. This fact is considered to be one of key factors that explains the obstinacy or recrudescence after radiotherapy. In view that hypoxic cells do not exist in normal tissues, it is very important to enhance the radiosensitivity of the hypoxic cells in tumor tissues in order to obtain better results from radiotherapy.
  • radiosensitizing agents selectively directed to hypoxic cells (hereinafter referred to simply as radiosensitizing agents) and agents having antiviral activity. They found that compounds of formula (I) have low toxicity, high radiosensitizing effect, and antiviral activity even at a low concentration. The low toxicity of the compound is notable because toxicity has long been the most serious problem in this technical field.
  • R 2 is acyl
  • compounds of formula (I) of this invention can be prepared, for example, by the following process: ##STR7## wherein R 4 represents an acyl group and R 1 has the same meaning as defined above.
  • compounds (Ia) of this invention can be prepared by reacting 1,3-diacyloxy-2-acyloxymethoxypropane (II) with a compound (III).
  • the starting compound (II) is readily obtainable according, for example, to a method described in Proc. Nat. Acad. Sci. USA 80, 4139 (1983) by A. K. Fielol et al.
  • the above reaction is carried out by melting a compound (II) and a compound (III) under a reduced pressure in the presence of a catalyst.
  • a catalyst As suitable catalyst, mention may be made of: protic acids such as p-toluenesulfonic acid, methanesulfonic acid and trichloroacetic acid; and Lewis acids such as anhydrous zinc chloride, anhydrous aluminum chloride and anhydrous stannic chloride.
  • the proportion of compound (II) and compound (III) may be varied arbitrarily. Generally, it is recommended that the compound (II) be used in equivalent or a little excessive amount.
  • the reaction temperature is preferably from 50° to 150° C.
  • the reaction is preferably completed in between 30 minutes to 6 hours, depending on reagent, solvent, temperature, reaction accelerator, etc.
  • compounds (Ia) of this invention can be obtained by reacting 1,3-diacyloxy-2-acyloxymethoxypropane (II) with compound (IV) which is sililated derivative of compound (III).
  • the compounds (IV) are readily obtainable by reacting their corresponding compounds (III) with excessive amounts of N,O-bis(trimethylsilyl)acetamide at room temperature or under heat while stirring. Unreacted silylation agents are removed by distillation under reduced pressure.
  • the reaction process according to this invention is carried out in the presence of a Lewis acid.
  • Various Lewis acids are usable, and specific examples include anhydrous stannic chloride, anhydrous aluminum chloride, anhydrous zinc chloride, etc. They are preferably used in a catalytic amount or equivalent amount of compound (II).
  • the proportion of compound (II) and compound (IV) may be varied arbitrarily. In general, it is recommended that the compound (II) be used in an equimolar or a slightly excessive amount with respect to compound (IV).
  • Various solvents can be used in this reaction, which include acetonitrile, methylene chloride, benzene, toluene, etc.
  • the reaction proceeds at temperatures ranging from -30° to +50° C., and generally under water cooling conditions or at room temperature.
  • the reaction is preferably completed in between 30 minutes to 6 hours, depending on reagent, solvent, temperature, reaction accelerator, etc.
  • the objective products are separated from the reaction mixture and purified according to a conventional method.
  • the reaction mixture is subjected to extraction process, followed by condensation after washing the extract, and the residue being purified by chromatography to obtain a compound (Ia) at a high yield.
  • deacylation process is such that proceeds in absolute alcohol containing sodium alcoholate or in absolute alcohol saturated with ammonia, at a temperature ranging from 0° C. to room temperature over a few hours to overnight.
  • suitable deacylation is hydrolysis in water-alcohol using an organic base such as triethylamine, pyridine, etc. at a temperature ranging from room temperature to 80° C.
  • suitable alcohol lower alcohols such as methanol, ethanol and propanol may be mentioned.
  • Compounds (I) of this invention have low toxicity as shown by the test below, and have excellent radio-sensitizing ability as well as antiviral activity. They are preferably dosed 5 minutes to 5 hours prior to irradiation either orally or non-orally. They may be formed into tablets, capsules, granules, powders, sapositories or injections together with excipients, stabilizers, preservatives, modifiers, etc. as required. The administration amount depends on the patient's age, the region where tumor is produced, species and types of tumor, conditions of the patient, etc., and is preferably 0.2 to 5.0 g/m 2 body surface.
  • mice of 5 week old were intravenously or intraperitoneally administered with various compounds each dissolved in a physiological saline or in a physiological saline containing 10% DMSO. The mice were observed over 14 days and 50% death rates (LD 50/14 ) were obtained. The results are shown in Table 1.
  • a mixture gas of 95% nitrogen and 5% carbon dioxide was passed through cell suspension.
  • Tested compound Compound (3), 1 mM
  • mice Balb/c mice
  • Tested compound compound (3), 200 mg/kg
  • Enhancement ratio was obtained from irradiation dose and reduction ratio of tumor cells.
  • Herpes simplex virus type I Herpes simplex virus type II
  • Vero monkey kidney cells
  • a sample conditioned to contain 2 ⁇ 10 5 /ml of vero cells was cultured at 37° C. in an atmosphere of 5% CO 2 for 1 day to obtain a monolayer sample.
  • the sample was infected by HSV virus diluted with PBS (phosphate buffer).
  • Compound (I) was dissolved in DMSO, then adjusted to have concentrations of 100 ⁇ g/ml, 50 ⁇ g/ml, 10 ⁇ g/ml, 5 ⁇ g/ml and 1 ⁇ g/ml by 2% FBS MEM, and served as test agents.
  • the culture cells were added with each agent separately and incubated at 37° C. in a CO 2 incubator for one day. The cytopathic effect was observed under microscope. Cells were stained by crystal violet and scored as follows:

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Abstract

A novel heterocyclic derivative of formula (I): ##STR1## wherein R1 represents ##STR2## and R2 represents hydrogen or acyl. When R2 is acyl, the derivative can be prepared, for example, by the following process: ##STR3## wherein R4 is acyl and R1 is ##STR4## The derivative is less toxic and has radiosensitizing activity and antiviral activity even at a low concentration.
Radiosensitizing agents and antiviral agents containing the derivative as active component are also disclosed.

Description

This is a division of application Ser. No. 247,376, filed on Sept. 21, 1988, now U.S. Pat. No. 4,945,102.
BACKGROUND OF THE INVENTION
1) Field of the Invention
This invention relates to a novel heterocyclic derivative of formula (I): ##STR5## wherein R1 represents ##STR6## and R2 represents a hydrogen atom or an acyl group; its preparation; and radiosensitizing agents and antiviral agents comprising the derivative as their active component.
2) Description of the Background Art
Hypoxic cells in tumor tissues are strongly resistant to radiation. This fact is considered to be one of key factors that explains the obstinacy or recrudescence after radiotherapy. In view that hypoxic cells do not exist in normal tissues, it is very important to enhance the radiosensitivity of the hypoxic cells in tumor tissues in order to obtain better results from radiotherapy.
Meanwhile, viral infectious diseases which attack mammals including humans are contagious and bring agony and economic loss to our society. Only limited viral infectious diseases are curable by currently available antiviral agents, and new synthetic antiviral agents stand in demand.
SUMMARY OF THE INVENTION
Under the above circumstances, the present inventors conducted intensive studies for developing agents capable of selectively sensitizing hypoxic cells without affecting the sensitivity of normal cells at the time of irradiation, in other words, radiosensitizing agents selectively directed to hypoxic cells (hereinafter referred to simply as radiosensitizing agents) and agents having antiviral activity. They found that compounds of formula (I) have low toxicity, high radiosensitizing effect, and antiviral activity even at a low concentration. The low toxicity of the compound is notable because toxicity has long been the most serious problem in this technical field.
Accordingly, it is an object of the invention to provide a heterocyclic derivative of formula (I) and a process for preparing the derivative. It is another object of the invention to provide a radiosensitizing agent and an antiviral agent comprising the derivative as their active component.
DETAILED DESCRIPTION OF THE INVENTION
When R2 is acyl, compounds of formula (I) of this invention can be prepared, for example, by the following process: ##STR7## wherein R4 represents an acyl group and R1 has the same meaning as defined above.
In other words, compounds (Ia) of this invention can be prepared by reacting 1,3-diacyloxy-2-acyloxymethoxypropane (II) with a compound (III). The starting compound (II) is readily obtainable according, for example, to a method described in Proc. Nat. Acad. Sci. USA 80, 4139 (1983) by A. K. Fielol et al.
The above reaction is carried out by melting a compound (II) and a compound (III) under a reduced pressure in the presence of a catalyst. As suitable catalyst, mention may be made of: protic acids such as p-toluenesulfonic acid, methanesulfonic acid and trichloroacetic acid; and Lewis acids such as anhydrous zinc chloride, anhydrous aluminum chloride and anhydrous stannic chloride. The proportion of compound (II) and compound (III) may be varied arbitrarily. Generally, it is recommended that the compound (II) be used in equivalent or a little excessive amount. The reaction temperature is preferably from 50° to 150° C. The reaction is preferably completed in between 30 minutes to 6 hours, depending on reagent, solvent, temperature, reaction accelerator, etc.
The compounds (Ia) of this invention can also be prepared according to the following process: ##STR8## wherein R4 as same as defined above and R5 represents ##STR9##
In other words, compounds (Ia) of this invention can be obtained by reacting 1,3-diacyloxy-2-acyloxymethoxypropane (II) with compound (IV) which is sililated derivative of compound (III).
The compounds (IV) are readily obtainable by reacting their corresponding compounds (III) with excessive amounts of N,O-bis(trimethylsilyl)acetamide at room temperature or under heat while stirring. Unreacted silylation agents are removed by distillation under reduced pressure.
The reaction process according to this invention is carried out in the presence of a Lewis acid. Various Lewis acids are usable, and specific examples include anhydrous stannic chloride, anhydrous aluminum chloride, anhydrous zinc chloride, etc. They are preferably used in a catalytic amount or equivalent amount of compound (II).
The proportion of compound (II) and compound (IV) may be varied arbitrarily. In general, it is recommended that the compound (II) be used in an equimolar or a slightly excessive amount with respect to compound (IV). Various solvents can be used in this reaction, which include acetonitrile, methylene chloride, benzene, toluene, etc. The reaction proceeds at temperatures ranging from -30° to +50° C., and generally under water cooling conditions or at room temperature. The reaction is preferably completed in between 30 minutes to 6 hours, depending on reagent, solvent, temperature, reaction accelerator, etc.
After the reaction is completed, the objective products are separated from the reaction mixture and purified according to a conventional method. For instance, the reaction mixture is subjected to extraction process, followed by condensation after washing the extract, and the residue being purified by chromatography to obtain a compound (Ia) at a high yield.
Going back to the general formula (I), compounds (I) having hydrogen as R2 can be prepared by deacylation of compounds (Ia) as shown below: ##STR10##
One example of the deacylation process is such that proceeds in absolute alcohol containing sodium alcoholate or in absolute alcohol saturated with ammonia, at a temperature ranging from 0° C. to room temperature over a few hours to overnight. Another example of suitable deacylation is hydrolysis in water-alcohol using an organic base such as triethylamine, pyridine, etc. at a temperature ranging from room temperature to 80° C. As suitable alcohol, lower alcohols such as methanol, ethanol and propanol may be mentioned.
Examples of the novel compounds (I) of this invention are:
(1) 1-[2-acetoxy-1-(acetoxymethyl)ethoxy]methyl-2-nitroimidazol,
(2) 1-[2-acetoxy-1-(acetoxymethyl)ethoxy]methyl-3-nitro-1,2,4-triazol,
(3) 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazol,
(4) 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-3-nitro-1,2,4-triazol.
In this specification, the above compounds (1) to (4) will hereinafter be referred to as compound (1), compound (2), compound (3) and compound (4).
Compounds (I) of this invention have low toxicity as shown by the test below, and have excellent radio-sensitizing ability as well as antiviral activity. They are preferably dosed 5 minutes to 5 hours prior to irradiation either orally or non-orally. They may be formed into tablets, capsules, granules, powders, sapositories or injections together with excipients, stabilizers, preservatives, modifiers, etc. as required. The administration amount depends on the patient's age, the region where tumor is produced, species and types of tumor, conditions of the patient, etc., and is preferably 0.2 to 5.0 g/m2 body surface.
Action and Effect
Acute toxicity test and other tests regarding radiosensitising ability and antiviral activity were carried out using the compounds of the present invention.
(1) Acute toxicity test
ICR strain male mice of 5 week old were intravenously or intraperitoneally administered with various compounds each dissolved in a physiological saline or in a physiological saline containing 10% DMSO. The mice were observed over 14 days and 50% death rates (LD50/14) were obtained. The results are shown in Table 1.
                                  TABLE 1                                 
__________________________________________________________________________
Compound      Dose                                                        
Nos.  Administration                                                      
              (mg/kg)                                                     
                   Dead/Treated                                           
                           LD.sub.50/14                                   
                                 General Status                           
__________________________________________________________________________
1     intraperitoneal                                                     
              720  0/2     >860  Clamed down                              
      "       860  0/2                                                    
2     intraperitoneal                                                     
              600  0/2      790  Transient respiratory accelera-          
      "       720  0/2           tion after administration, then          
      "       860  2/2           calmed down                              
3     intravenous                                                         
              720  0/2     >860  Calmed down                              
      "       860  0/2                                                    
4     intravenous                                                         
              720  0/2      860  Calmed down                              
      "       860  1/2                                                    
__________________________________________________________________________
(2) Radiosensitivity test (a) In vitro test 1
Cells used in the test: single cells of EMT-6
Irradiation: 60 Co - gamma rays
Cell treatment to hypoxia:
A mixture gas of 95% nitrogen and 5% carbon dioxide was passed through cell suspension.
Survival ratio of cells:
Determined by counting colonies.
Radiosensitivity enhancement ratio (ER): ##EQU1## The results of this test are shown in Table 2.
              TABLE 2                                                     
______________________________________                                    
Compound Nos.  Concentration (mM)                                         
                             ER                                           
______________________________________                                    
3              1.0           1.70                                         
4              1.0           1.50                                         
______________________________________
(b) In vitro test 2
Cells used in the test: Spheroids of EMT-6
Irradiation: 60 Co - gamma rays
Tested compound: Compound (3), 1 mM
Determination of radiosensitivity enhancement:
Six particles of spheroid having a certain size were taken and placed in a culture solution containing compound 3) having a concentration of 1 mM, and incubated at 37° C. over 30 to 60 minutes, followed by irradiation. The spheroids were treated by trypsin and then the enhancement ratio (ER) was obtained by counting colonies.
The result obtained was: ER of compound (3) at a concentration of 1 mM=1.55
(c) In vivo test
Animal: Balb/c mice
Tumor: EMT-6
Tested compound: compound (3), 200 mg/kg
Administration:
Compound (3) dissolved in a physiological saline was intraperitoneally administered 20 minutes prior to irradiation.
Irradiation: 60 Co - gamma rays,
whole body irradiation,
Determination of radiosensitivity enhancement:
Enhancement ratio (ER) was obtained from irradiation dose and reduction ratio of tumor cells.
The result obtained was: ER of compound (3) (200 mg/kg)=1.55
(3) Antiviral activity test
Virus: Herpes simplex virus type I
Cells: Vero (monkey kidney cells)
Culture medium: 2% FBS MEM
A sample conditioned to contain 2×105 /ml of vero cells was cultured at 37° C. in an atmosphere of 5% CO2 for 1 day to obtain a monolayer sample. The sample was infected by HSV virus diluted with PBS (phosphate buffer). Compound (I) was dissolved in DMSO, then adjusted to have concentrations of 100 μg/ml, 50 μg/ml, 10 μg/ml, 5 μg/ml and 1 μg/ml by 2% FBS MEM, and served as test agents. The culture cells were added with each agent separately and incubated at 37° C. in a CO2 incubator for one day. The cytopathic effect was observed under microscope. Cells were stained by crystal violet and scored as follows:
0: almost all cells are dead
1: certain effect of the agent with some dead cells
2: normal
The results are shown in Table 3.
              TABLE 3                                                     
______________________________________                                    
          100      50      10     5     1                                 
Compound Nos.                                                             
          μg/ml μg/ml                                               
                           μg/ml                                       
                                  μg/ml                                
                                        μg/ml                          
______________________________________                                    
3         2        2       1      0     0                                 
4         2        2       1      0     0                                 
______________________________________
EXAMPLES
This invention may be more fully understood from the following examples.
EXAMPLE 1 1-[2-acetoxy-1-(acetoxymethyl)ethoxy]methyl-2-nitroimidazol: compound (1)
5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%).
MS(m/e): 301(M+)
IR(cm-1): 1740 (CO), 1535 (NO2), 1490 (NO2)
NMR(δ, CDCl3) 2.0 (s, 6H, CH3 CO x 2), 3.8-4.3 (m, 5H, --CH2 OAc x 2, >CH--), 5.9 (s, 2H, --OCH2 N<), 7.1 (s, 1H, ring proton), 7.4 (s, 1H, ring proton)
EXAMPLE 2 1-[2-acetoxy-1-(acetoxymethyl)ethoxy]methyl-3-nitro-1,2,4-triazol: compound (2)
General procedures of Example 1 were followed to obtain the title compound as a viscous oil material (yield: about 83%).
MS(m/e): 302(M+)
IR(cm-1) 1740 (CO), 1555 (NO2), 1500 (NO2),
NMR(δ, CDCl3): 2.0(s, 6H, CH3 CO x 2), 3.8-4.3 (m, 5H, --CH2 OAc x 2, >CH--), 5.9 (s, 2H, --OCH2 N>), 8.7 (s, 1H, ring proton)
EXAMPLE 3 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2nitroimidazol: compound (3)
3.01 g of 1-[2-acetoxy-1-(acetoxynethyl)ethoxy]- methyl-2-nitroimidazol (compound (1)) was dissolved in 50 ml of absolute methanol, and stirred at room temperature while being added with 5% absolute ethanol solution of sodium ethoxide dropwise until pH reached 9.0. Stirred at room temperature over 3 hours. Then Dowex 50 W (H+, made by Dow Chemical) was slowly added until the liquid had a pH of 7.0. Dowex 50 W was removed by suction filtration, and the solvent was distilled off under reduced pressure. The residue was subjected to recrystallization by ethanol to obtain 2.83 g of the title compound as light yellow needles (yield: 94%).
Melting point: 88° C.
MS(m/e): 218 (M+1), 185, 114, 98
IR(cm-1): 3450 (OH), 1540 (NO2), 1490 (NO2)
NMR [δ, DMSO(d6)]: 3.2-3.6 (m, 5H, --CH2 OH x 2, >CH--), 4.6 (t, 2H, OHx 2), 5.9(s, 2H, --OCH2 N>), 7.15(s, 1H, ring proton), 7.8 (s, 1H, ring proton)
EXAMPLE 4 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-3-nitro-1,2,4-triazol: compound (4)
General procedures of Example 3 were followed to obtain the title compound as colorless needles (yield: 95%).
Melting point: 132° C.
MS(m/e): 219 (M+1), 205, 185
IR(cm-1): 3450 (OH), 1560 NO2), 1500 (NO2)
NMR[δ, DMSO(d6)]: 3.3-3.8 (m, 5H, --CH2 OH x 2, >CH--), 4.6 (t, 2H, OHx 2), 5.8 (s, 2H, --OCH2 N>), 9.0 s, 1H, H in 5th position)

Claims (3)

What is claimed is:
1. A heterocyclic derivative of the following formula (I): ##STR11## wherein R1 represents ##STR12## and R2 represents a hydrogen atom or an acetyl group.
2. A radiosensitizing composition comprising as its active component a radiosensitizing effective amount of a heterocyclic derivative of formula I: ##STR13## wherein R1 represents ##STR14## and R2 represents a hydrogen atom or an acetyl group.
3. An antiviral composition comprising as its active component an antiviral effective amount of a heterocyclic derivative of the formula (I): ##STR15## wherein R1 represents ##STR16## and R2 represents a hydrogen atom or an acetyl group.
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US5535785A (en) * 1994-09-08 1996-07-16 Nypro, Inc. Luer-activated check valve
US6057453A (en) * 1995-03-31 2000-05-02 Florida State University Pharmaceutical compounds comprising polyamines substituted with electron-affinic groups
US6331286B1 (en) 1998-12-21 2001-12-18 Photogen, Inc. Methods for high energy phototherapeutics
US20020001567A1 (en) * 1998-12-21 2002-01-03 Photogen, Inc. Intracorporeal medicaments for high energy phototherapeutic treatment of disease
WO2006009901A2 (en) 2004-06-18 2006-01-26 Ambrx, Inc. Novel antigen-binding polypeptides and their uses
US20070093432A1 (en) * 2005-10-21 2007-04-26 California Pacific Medical Center Camptothecin derivatives as chemoradiosensitizing agents
US20070208076A1 (en) * 1998-12-21 2007-09-06 Dees H C Intracorporeal medicaments for high energy phototherapeutic treatment of disease
US7384623B1 (en) 1998-12-21 2008-06-10 Provectus Pharmatech, Inc. High energy phototherapeutic agents
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KR960011379B1 (en) 1996-08-22
DE3868308D1 (en) 1992-03-19
KR890006599A (en) 1989-06-14
JPH01110675A (en) 1989-04-27
JPH0819111B2 (en) 1996-02-28
EP0312858A1 (en) 1989-04-26
CA1329392C (en) 1994-05-10

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